Down syndrome, also known as Trisomy 21, is the first genetic cause of mental retardation in man. It is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21, causing delays in the way a child develops, both mentally and physically. Most text books quote the incidence of Down syndrome to be between one in 700 to 800 live births.
In addition to various physical characteristics, Down syndrome is often, though not always, characterized by varying degrees of cognitive impairment-impairment in memory, learning capacity or both. While advances in teaching methods and a trend toward educational mainstreaming has led to an improvement in cognitive development in those who have Down syndrome, there remain constitutive impairments that cannot be fully addressed through pedagogic methodology alone.
In addition, people with Down syndrome are at increased risk for certain medical problems. Some of the problems commonly faced by people with Down syndrome include heart defects, thyroid, muscle, joint, vision and hearing problems. Other conditions seen less frequently in Down syndrome include leukemia, and seizures. A variety of different approaches are used to treat these medical conditions. For example, if a person with Down syndrome has a seizure disorder, they would benefit from taking anti-seizure medications. People with thyroid problems often take thyroid replacement hormones. While these medications help with their medical condition, they do not cure Down syndrome.
Attempts at elaborating drugs for enhancing cognitive function in Down syndrome patients have been made. For example, piracetam is widely used as a purported means of improving cognitive function in children with Down syndrome. However, there have been reports undermining the proposition that piracetam may be effective in improving cognitive function in children with Down syndrome. (Lobaugh N J et al. Piracetam does not enhance cognitive abilities in moderate to high-functioning 7 to 13 year-old children with Down syndrome. Presented at the PAS/SPR meeting in San Francisco May 3, 1999; published in Archives of Ped and Adol Med, April 2001, 155(4):442-448 [ref 4]). In that study, neither cognitive nor behavioural measures demonstrated improvement under piracetam, even at doses associated with adverse effects.
Like Down syndrome patients, Ts65Dn mice, a murine model of Down syndrome carrying a segmental duplication of part of mouse chromosome 16, orthologous to most of the long arm of human chromosome 21, demonstrate learning and memory deficits, which are hypothetically due to selective decreases in the number of excitatory synapses in the brain rather than gross abnormalities in neuroanatomy. Theoretically, triplicate genes found in the Ts65Dn mice shift the optimal balance of excitation and inhibition in the dentate gyms (and other parts of the brain, perhaps) to a state in which excessive inhibition obscures otherwise normal learning and memory Reeves et al., Nature Genetics, 11(2):177-84 (1995) [ref 1].
It has recently been shown that use of GABAA antagonists in Ts65Dn mice increases memory, learning and neuronal plasticity (as assessed by long-term potentiation (LTP) protocols (Kleschevnikov et al., The Journal of Neuroscience, 24(37):8153-8160 (2004); [ref 2]). More recently, it has been shown that use of GABAA antagonists in a murine model of Down syndrome (Ts65Dn mice) normalized memory and declarative learning deficits as compared to euploid mice. (F. Fernandez et al., “Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome,” Nature Neuroscience, Advance Online Publication, (Feb. 25, 2007; [ref 3]).
These studies suggested the potential application of GABAA antagonist for restoring learning and memory performances in Down syndrome subjects.
Unfortunately, many GABAA antagonists tend to cause seizure in animal models as well as humans, making it clear that they cannot be used as cognition enhancing agents in subjects.
There is a large unmet medical need for the treatment of cognitive impairments associated with Down syndrome. Despite continued work, no notable medical treatments for mental retardation associated with Down syndrome have been forthcoming. Currently, medicines are not used to treat Down syndrome, rather medicines are used to treat other diseases associated with Down syndrome and other health conditions that may develop, such as antibiotics for ear infections and thyroid hormones for an underactive thyroid gland (hypothyroidism).
Thus, there is a need for a non-seizure inducing therapeutic treatment of cognitive impairments, such as impairment in memory, learning capacity or both, in subjects suffering from Down syndrome. The present invention meets this need and provides related advantages as well.